SELVA: A Multicenter, Phase 3 Baseline-Controlled Study Evaluating the Safety and Efficacy of PTX-022 in the Treatment of Microcystic Lymphatic Malformations

FOA Number: RFA-FD-23-001 FOA Title: Clinical Studies of Orphan Products Addressing Unmet Needs of Rare Diseases (R01) Clinical Trials Required Proposal Title: SELVA: A Multicenter, Phase 3 Baseline-Controlled Study Evaluating the Safety and Efficacy of PTX- 022 in the Treatment of Microcystic Lymphatic Malformations

Institute: FDA Office of Orphan Products Development Study Section: N/A Summary The objective of this project is to demonstrate the safety and efficacy of PTX-022 (sirolimus) Topical Gel 3.9% w/w for patients suffering from microcystic lymphatic malformations (microcystic LM). Microcystic LM is a serious, rare, and

chronic disease of the lymphatic system characterized by lymphorrhea, acute cellulitis and significant patient morbidity. Microcystic LM is an orphan disease with no FDA approved therapies and there is an urgent need to develop the first FDA approved therapy to treat this debilitating disease. Microcystic LM is usually present at birth or shortly after, with the pathology often originating in the dermis and

protruding out through the epidermis and stratum corneum. Recent studies have identified that patients with microcystic LM have postzygotic mutations in PI3K leading to abnormal and increased activation in mTOR signaling as well as its downstream target vascular endothelial growth factor (VEGF). Oral sirolimus, an mTOR inhibitor which is also known as

rapamycin, has demonstrated preliminary benefit in patients with microcystic LM but its use is limited by the adverse event profile, requirement for frequent blood monitoring, and limited distribution to the skin. Therefore, Palvella Therapeutics, Inc. (Palvella) is developing PTX-022, a 3.9% topical sirolimus gel designed to deliver high levels of

sirolimus directly to the site of disease, the epidermis and dermis, while avoiding the systemic side effects of oral sirolimus. PTX-022 recently completed a Phase 2, 12 patient, open-label clinical study (NCT05050149). Efficacy data

from the Phase 2 study demonstrated statistically significant and clinically meaningful improvements with patients treated with PTX-022. All twelve patients who entered the study were either “much improved” (n=7, 58%) or “very much improved” (n=5, 42%) on the clinician global impression of change (CGI-C) and all twelve patients improved on the

patient global impression of change (PGI-C). Based on the Phase 2 data, FDA awarded PTX-022 Breakthrough Therapy Designation for the treatment of microcystic LM. Breakthrough Therapy Designation is intended to expedite the development and review of therapies for serious or life-threatening conditions and whose preliminary clinical evidence indicates that the drug may demonstrate substantial

improvement on one or more clinically significant endpoints over existing therapies. Following a collaborative Type B Meeting with FDA in April 2024, Palvella is advancing the development of PTX-022 into a registrational Phase 3 study in patients with microcystic LM. Primary efficacy will be assessed using a fit for purpose microcystic LM Investigator

Global Assessment (mLM-IGA) scale. The secondary objectives are to determine the efficacy of once-daily treatment

with PTX-022 utilizing scores from the clinician microcystic LM multicomponent severity scale, the overall patient global impression of change (PGI-C) scores, and the overall clinical global impression of severity (CGI-S) scale. Importantly, exit and entry qualitative interviews will be conducted for each patient to determine burden of disease and clinical

meaningfulness of any changes observed. In addition to Breakthrough Designation, PTX-022 has been granted Fast Track Designation and Orphan Drug Designation by the FDA for microcystic LM. Grant funding, if awarded, will be used to directly support the initiation, enrollment, and completion of the Phase 3 clinical trial and support NDA submission and FDA approval. This proposal

aims to fulfill the goal of the FDA’s Office of Orphan Product Development grant program to support the clinical development of products for use in rare diseases where no therapy currently exists.